Derivatives of



United States Patent 015 3,1l33fi18 DERIVATEVES F 3,l-DKHYDRQ-Zfi-1,2,4-BENZO- THIADIAZINE 1,1-Dl0XlDES Harold BaldingMaelhillamy, Madison, and Geargc dc Stevens, Willow Kncll, NewProvidence, NJ, assignors to Cilea (forporation, a corporation ofDelaware No Drawing. Filed Apr. 20, 1960, Ser. No. 23,373

Claims. (Cl. 260-243) The present invention concerns2-substituted-3,4-dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxides. Moreparticularly, it relates to compounds of the formula (S32 HzNOgS CHE-R1R3 N/ 1 RBI] in which R represents hydrogen, aliphatic hydrocarbon,substituted aliphatic hydrocarbon, carbocyclic aryl, carbocyclicaryl-lower aliphatic hydrocarbon, heterocyclic aryl or heterocyclicaryl-lower aliphatic hydrocarbon, R stands for lower cycloalkylcontaining oxygen and/or sulfur atoms as ring members and advantageouslyhave from four to six carbon atoms and at most two atoms selected fromthe group consisting of sulfur and oxygen as ring members, R representshydrogen or lower alkyl, and R stands for halogen, lower alkyl orhalogenolower alkyl or salts thereof, as well as process for thepreparation of such compounds.

Apart from being hydrogen, R may also stand for aliphatic hydrocarbonradicals, for example, lower aliphatic hydrocarbon, such as lower alkyl,e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl,tertiary butyl, pentyl, isopentyl, neopentyl and the like, loweralkenyl, e.g. vinyl, l-propenyl, allyl and the like, lower alkynyl, e.g.ethynyl and the like carbocyclic aliphatic hydrocarbons, particularlymonocyclic carbocyclic aliphatic hydrocarbons, which contain from threeto seven carbon atoms, as ring members and in which the carbocyclicportion may be saturated or may contain from one to two double bondsdepending on the number of ring carbon atoms, such as cycloalkyl, whichcontains from five to six ring carbon atoms, e.g. cyclopentyl,cyclohexyl and the like, or cycloalkenyl, which contains from five tosix carbon atoms as ring members, e.g. 2 cyclopentenyl, 3 cyclopentenyl,2 cyclohexenyl, 3- cyclohexenyl and the lke, or carbocyclic aliphatichydrocarbon-lower aliphatic hydrocarbon, primarily monocycliccarbocyclic aliphatic hydrocarbon-lower alkyl, which contains from threeto seven carbon atoms as ring members and in which the carbocyclicportion may be saturated or contain from one to two double bondsdepending on the number of ring carbon atoms, and in which lower alkylrepresents a lower alkylene radical containing from one to seven,particularly from one to three, carbon atoms, such as cycloalkyl-loweralkyl radicals, which contain from five to six carbon atoms as ringmembers, e.g. cyclopentylmethyl, l-cyclopentylethyl, 2 cyclopentylethyl,1 cyclopentylpropyl, 3 cyclopentylpropyl, cyclohexylmethyl, 1cyclohexylethyl, 2 cyclohexylethyl, l-cyclohexylpropyl,3-cyclohexylpropyl and the like, or cycloalkenyl-lower alkyl radicals,when con- 3,133,918 Patented May 19, 1964 ice tain from five to six ringcarbon atoms, e.g. 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, 2 (2cyclopentenyl) ethyl, 2 cyclohexenylmethyl, 3 cyclohexenylmethyl,1-(3-cyclol1exenyl) ethyl, 2 (2 cyclohexenyl)- ethyl,3-(2-cyclohexenyl)-propyl and the like.

These aliphatic hydrocarbon radicals may contain functional groups asadditional substituents. Such substituents are primarily attached tolower alkyl radicals, which may be represented by a lower alkyleneradical containing from one to live carbon atoms, such as, for example,methylene, 1,1-ethylene, 1,2-ethylene, l,1-dimethyl-1,2- ethylene,1,1-propylene, 1,2-propylene, 1,3-propylene, 2,3- propylene,2,2propylene, 1,1-butylene, 1,2-butylene, 1,3- butylene, 1,4-butylene,2,2-butylene, 2,3-butylene, 1,5- pentylene, 2,5-pentylene and the like.

substituents are, for example, one or more than one halogen atom, e.g.fluorine, bromine, or particularly chlorine; halogeno-substituted loweralkyl radicals, representing R are, for example, trifluorornethyl,chloromethyl, 2-chloroethyl, dichloromethyl, trichloromethyl,bromomethyl and the like.

Other substituents are amino groups, such as primary amino groups,secondary amino groups, such as N-lower alkyl-amino, e.g. N-methylamino,N-ethylamino and the like, N-carbocyclic arylamino, e.g. N-phenylaminoand the like, or N-carbocyclic aryl-lower alkyl-amino, e.g.N-benzylamino and the like, or primarily tertiary amino groups,particularly N,N-di-lower alkylamino, in which lower alkyl contains fromone to seven carbon atoms, e.g. N,N-dimethylamino,N-ethyl-N-methyl-amino, N,N- diethylamino, N,N dipropylamino, N,N diisopropylamino, N,N-dibutylamino and the like, N-cycloalkyl-N- loweralkyl amino, e.g. N-cyclopentyl-N-methyl-amino,N-cyclohexyl-N-methyl-amino and the like, N carbocyclic aryl lower alkylN lower alkyl amino, e.g. N- benzyl-N-rnethyl-amino, N-methy N (2phenylethyl)- amino and the like, 1-N,N-lower alkylene-imino group, inwhich the lower alkylene radical contains from four to six carbon atoms,such as l-pyrrolidino, e.g. l-pyrrolidino, Z-methyl-l-pyrrolidino andthe like, l-piperidino, e.g. 1 piperidino, 2 methyl 1 piperidino,3-methyl-1- piperidino, 4 methyl 1 piperidino, 3 hydroxy 1- piperidino,3-acetoxy 1 piperidino, 3-hydroxymethyl-1 piperidino and the like, orl-N,N-hexamethylene-imi11o, l-N,N-lower oxa-a1kylene-imino, in whichoxa-alkylene contains preferably four carbon atoms, e.g. l-morpholinoand the like, or l-N,N-lower aza-alkylene-imino, in which aza-alkylenecontains preferably four carbon atoms, e.g. l-piperazino, 4-methyl 1piperazino, 4 hydroxyethyl-lpiperazino, 4-acetoxyethyl-l-piperazino andthe like. The teritary amino group and the lower alkyl radical to whichthe amino group is attached may present together a heterocyclic radical,in which the tertiary amino group is part of the heterocycle and one ofthe carbon atoms of the heterocyclic ring is connected directly orthrough a lower alkylene radical, e.g. methylene or 1,2-ethylene, withthe 3-position of the 1,2,4-thiadiazine 1,1- dioxide portion. Suchradicals are, for example, 1-methyl-3-pyrrolidinomethyl, l-methyl 3piperidinomethyl, 2-(l-methyl-2- piperidino)-ethyl,1-methyl-4-piperidino and the like.

Other substituents attached to aliphatic hydrocarbon,

particularly lower alkyl, radicals are also N-acylamino groups, in whichacyl represents the acyl radical of an organic carboxylic acid, forexample, a substituted carbonic acid, e.g. methoxy-carbonic acid,ethoxy-carbonic acid, benzyloxy-carbonic acid and the like, a loweraliphatic carboxylic acid, such as a lower alkanoic acid, e.g. acetic,propionic, pivalic acid and the like, lower alkenoic acids, e.g.acrylic, methylacrylic acid and the like, lower aliphatic dicarboxylicacids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaricacid and the like, or their halfesters with lower alkanols, e.g.methanol, ethanol and the like, carbocyclic aryl-carboxylic acids,particularly monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoicor substituted benzoic acids, carbocyclic aryl-lower aliphaticcarboxylic acids, particularly monocyclic carbocyclic aryl-lower alkylcarboxylic acids, e.g. phenylacetic, diphenylacetic, dihydrocinnamicacid and the like, which may contain additional substituents in thearomatic portion, or monocyclic carbocyclic aryllower alkenyl carboxylicacids, e.g. cinnamic acid or substituted cinnamic acids; substituentsattached to these carboxylic acids are, for example, lower alkyl, e.g.,methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and thelike, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino,particularly tertiary amino, such as N,N-di-lower alkyl-amino, e.g.N,N-dimethylamino, N, N-diethylamino and the like, halogen, e.g.fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g.trifiuoromethyl.

Acyl groups are additional substituents of aliphatic hydrocarbon,particularly lower alkyl radicals, primarily acyl radicals of organiccarboxylic acids, such as lower alkanoic acid, e.g. acetic, propionic,butyric acid and the like, as well as substituted carbonic acids, e.g.methoxycarbonic acid, ethoxy-carbonic acid, benzyloxy-carbonic acid andthe like, lower alkenoic acids, e.g. acrylic, methacrylic acid and thelike, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic,succinic, glutaric, adipic, maleic, fumaric acid and the like, or theirhalfesters with lower alkanols, e.g. methanol, ethanol and the like,carbocyclic aryl-carboxylic acids, primarily monocyclic carbocyclicaryl-carboxylic acids, e.g. benzoic or substituted benzoic acids,carbocyclic aryl-lower aliphatic carboxylic acids, primarily monocycliccarbocyclic aryl-lower alkyl carboxylic acids, e.g. phenylacetic,dihydrocinnamic acid and the like, which may contain additionalsubstituents in the aromatic portion, or monocyclic carbocyclicaryllower alkenyl carboxylic acids, e.g. cinnamic acid and the like, orsubstituted cinnamic acids. Additional substituents of these carboxylicacids are, for example, lower alkyl, e.g. methyl, ethyl and the like,lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy,e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such asdi-lower alkylamino, e.g. N,N-dimethylamino, N,N-diethylamino and thelike, halogen, e.g. fluorine, chlorine, bromine and the like, orhalogenolower alkyl, e.g. trifiuoromethyl.

Other substituents attached to aliphatic hydrocarbon, particularly loweralkyl radicals, are hydroxyl groups. Esterified hydroxyl groups may alsobe suitable as substituents, especially hydroxyl groups esterified byorganic carboxylic acids, for example, substituted carbonic acids, e.g.methoxy-carbonic, ethoxy-carbonic, benzyloxy-carbonic and the like,lower aliphatic carboxylic acids, such as lower alkanoic acids, e.g.acetic, propionic, pivalic acid and the like, lower alkenoic acids, e.g.acrylic, methylaerylic acid and the like, lower aliphatic dicarboxylicacids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaricacid and the like, or their haltesters with lower alkanols, e.g.methanol, ethanol and the like, carbocyclic aryl-carboxylic acids,primarily monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic orsubstituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylicacids, primarily monocyclic carbocyclic aryl-lower alkyl carboxylicacids, e.g. phenylacetic, dihydrocinnamic acid and the like, which maycontain additional substituents in the aromatic portion, or monocycliccarbocyclic aryllower alkenyl carboxylic acids, e.g. cinnamic acid andthe like, or substituted cinnarnic acids. Substituents of suchcarboxylic acids, are, for example, lower alkyl, e.g. methyl, ethyl andthe like, lower alkoxy, e.g. methoxy, ethoxy and the like, loweralkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiaryamino, such as di-lower alkyl-amino, e.g. N,N-dimethylamino,N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromineand the like, or halogeno-lower alkyl, e.g. trifluoromethyl.

Further substituents of aliphatic hydrocarbon radicals, particularlylower alkyl radicals, are etherified hydroxyl groups, which may berepresented, for example, by aliphatic hydrocarbonoxy, such as loweralkoxy, e.g. methoxy, ethox n-propyloxy, isopropyloxy, n-butyloxy,isobutyloxy and the like, lower alkenyloxy, e.g. vinyloxy, allyioxy andthe like, carbocyclic aryloxy, such as monocyclic carbocylic aryloxy,e.g. phenyloxy or substituted phenyloxy, or bicyclic carbocyclicaryloxy, e.g. l-naphthyloxy or Z-naphthyloxy or substituted naphthyloxy,or carbocyclic aryl-aliphatic hydrocarbonoxy, such as monocycliccarbocyclic aryl-lower alkoxy, e.g. benzyloxy or substituted benzyloxy.The aliphatic hydrocarbon, and particularly the carbocyclic arylportions of the etherified hydroxyl groups may contain additionalsubstituents; such substituents are, for example, lower alkyl, e.g.methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and thelike, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino,particularly tertiary amino, such as N,N-di-lower alkyl-amino, e.g.N,N-dimethylamino, N,N- diethylamino and the like, halogen, e.g.fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g.trlfluoromethyl.

in addition, aliphatic hydrocarbon, particularly lower alkyl, radicalsmay be substituted by an etherified mercapto group, for example,aliphatic hydrocarbon-mercapto, such as lower alkyl-mercapto, e.g.methyl-mercapto, ethyl-mercapto, n-propyl-mercapto, isopropylmercapto,n-butyl-mercapto, isobutyl-mercapto and the like, loweralkenyl-mercapto, e.g. vinyl-mercapto, allylmercapto and the like,carbocyclic aryl-mercapto, such as monocyclic carbocyclic aryl-mercapto,e.g. phenylmercapto or substituted phenyl-mercapto, or bicycliccarbocyclic aryl-mercapto, e.g. l-naphthyl-mercapto orZ-naphthyl-mercapto or substituted naphthyl-mercapto, or carbocyclicaryl-aliphatic hydrocarbon-mercapto, primarily monocyclic carbocyclicaryl-lower alkyl-mercapto, e.g. benzyl-mercapto, l-phenylethyl-mercapto,2-phenylethyl-mercapto and the like, or substituted benZyl-mercapto,substituted l-phenylethyl-mercapto, substituted 2- phenylethyl-mercaptoand the like. The aliphatic hydrocarbon portions and, particularly, thecarbocyclic aryl portions of the etherified mercapto groups may containadditional substituents; such substituents are, for example, loweralkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy,ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro,amino, such as primary or secondary amines, or, particularly, tertiaryamino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino,N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromineand the like, halogeno-lower alkyl, e.g. trifluoromethyl.

Apart from aliphatic hydrocarbon radicals R may represent carbocyclicaryl groups, such as monocycle carbocyclic aryl, e.g. phenyl orsubstituted phenyl, or monocyclic carbocyclic aryl, e.g. l-naplithyl orZ-naphthyl or substituted naphthyl radicals, or carbocyclicarylaliphatic hydrocarbon radicals, particularly monocyclic or bicycliccarbocyclic aryl-lower alkyl, e.g. benzyl, lphenylethyl, Z-phenylethyl,3-pl1enylpropyl, l-naphylmethyl and the like, or these radicalssubstituted in the carbocyclic aryl portion, or monocyclic or bicycliccarbocyclic aryl-lower alkenyl, e.g. 2-phenyl-ethenyl and the like, aswell as such radicals containing in the carbocyclic portion additionalsubstituents. Such substituents are, for example, lower alkyl, e.g.methyl, ethyl and the like,

lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy,e.g. methylenedioxy, lower alkyl mercapto, e.g. methylmercapto and thelike, amino, particularly tertiary amino, such as N,N-di-loweralkyl-amino, e.g. dimethylamino and the like, halogen, e.g. fluorine,chlorine, bromine and the like, or halogeno-lower alkyl, e.g.trifluoromethyl. Substituents attached to carbocyclic aryl, particularlymonocyclic carbocyclic aryl portions may be in any of the availablepositions, whereby one or more than one of the same or of diiferentsubstituents may be present.

Additional groups representing R are heterocyclic aryl radicals,particularly monocyclic or bicyclic heterocyclic aryl radicals, whichmay contain from five to six atoms as ring members in the heterocyclicportion, such as pyridyl, e.g. Z-pyridyl, 3-pyridyl, 4-pyridyl and thelike, thienyl, e.g. 2-thienyl and the like, furyl, e.g. 2-furyl and thelike, or quinolyl, e.g. 6-quinolyl and the like, or heterocyclicaryl-aliphatic hydrocarbon, such as monocyclic heterocyclic-aryl-loweralkyl, for example, thenyl, e.g. Z-thenyl and the like. These radicalsmay contain additional substituents, particularly lower alkyl, e.g.methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and thelike, or halogen, e.g. fluorine, chlorine, bromine and the like.

The radical R stands for lower cycloalkyl containing oxygen and/orsulfur atoms as ring members. These groups have advantageously from fourto six carbon atoms and at most two atoms selected from the groupconsisting of sulfur and oxygen as ring members.

The carbon atoms of the lower cycloalkyl nucleus may be unsubstituted orsubstituted by lower hydrocarbon, particularly lower alkyl, e.g. ethyl,n-propyl, isopropyl, or especially methyl and the like; othersubstituents may be, for example, lower cycloalkyl, e.g. cyclopentyl orcyclohexyl and the like, monocyclic or bicyclic carbocyclic aryl, e.g.phenyl or naphthyl, monocyclic or bicyclic carbocyclic aryl-lower alkyl,e.g. benzyl, l-phenylethyl or Z-phenylethyl and the like. Two of thecarbon atoms of the lower cycloalkyl nucleus may also be part of asecond carbocyclic ring system fused onto the lower cycloalkyl nucleus;such carbocyclic ring systems may be represented, for example, by lowercycloalkyl containing from five to seven carbon atoms, e.g. cyclopentyl,cyclohexyl or cycloheptyl and the like, or carbocyclic aryl, such asmonocyclic or bicyclic carbocyclic aryl, e.g. phenyl or naphthyl.

The cycloalkyl radical, R may, therefore, be represented primarily bycyclo-oxa-alkyl containing from four to six carbon atoms, such attetrahydrofuranyl (cyclooxapentyl) radicals, such as Z-tetrahydrofuranyl(2-cyclooxapent-yl) radicals, e.g. 2-tetrahydrofuranyl (2-cyclooxapentyl), 4-methyI-Z-tetrahydrofuranyl (4 methyl 2- cyclo-oxapentyl)or S-methyl-Z-tetrahydrofuranyl (5- methyl-2-cyclo-oxapentyl) and thelike, tetrahydropyranyl (cyclo-oxahexyl) radicals, such asZ-tetrahydropyranyl (Z-cyclo-oxahexyl) radicals, e.g.Z-tetrahydropyranyl (2- cyclo-oxahexyl), 2-methyl-2-tetrahydropyranyl(2-methyl 2-cyclo-oxahexyl), 4 methyl 2 tetrahydropyranyl (4-methyl-Z-cyclo-oxahexyl), 6-rnethyl-2-tetrahydropyranyl(6-methyl-2-cyclo-oxahexyl), 6 phenyl 2 tetrahydro pyranyl (6 phenyl 2cyclo oxahexyl), 2-hexahydrobenz [e] tetrahydropyranyl (bicyclo [4,4,0]-2-oxa-3-decyl or 2 benz[e]tetrahydropyranyl (2 benz[e]cyclo oxahexyl)and the like, cyclo-oxaheptyl radicals, such as 2-cyclo-oxaheptylradicals, e.g. Z-cyclo-oxaheptyl, and the like, dioxanyl(cyclo-dioxahexyl) radicals, such as 2-( 1,4-dioxanyl)(2-cyclo-dioxahexyl) radicals, e.g. 2- (l,4-dioxanyl)(2-cyclo-l,4-dioxahexyl) and the like, tetrahydro-oxathiinyl(cyclo-oxathiahexyl) radicals, such as 2 tetrahydro oxathiinyl(2-cyclo-1,4-oxathiahexyl) radicals, e.g. Z-tetrahydro-oxathiinyl(2-cyclo-l,4-oxathiahexyl) and the like, tetrahydrothienyl(cyclo-thiapentyl) radicals, such as Z-tetrahydrothienyl(Z-cyclothiapentyl) radicals, e.g. Z-tetrahydrothienyl and the like,

tetrahydro-thiapyranyl (cyclo-thiahexyl) radicals, such as2tetrahydro-thiapyranyl (2 cyclo thiahexyl) radicals, e.g.Z-tetrahydro-thiapyranyl (Z-cyclo-thiahexyl) and the like, ortetrahydro-dithiinyl (cyclo-dithiahexyl) radicals, such asZ-tetrahydro-dithiinyl (2-cyclo-1,4-dithiahexyl) radicals, e.g.Z-tetrahydro-dithiinyl (2-cyclo-l,4-dithiahexyl) and the like.

The radical R attached to the second, aniline-type amino group of the1,2,4-thiadiazine portion of the compounds of this invention, representsprimarily hydrogen, but may also stand for lower alkyl, e.g. methyl,ethyl and the like.

The group R attached to the 6-position of the3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide, stands for halogen,e.g. fluorine, bromine, or particularly chlorine and the like, loweralkyl, e.g. methyl and the like, or halogeno-lower alkyl, particularlytrifluoromethyl and the like.

Salts of the compounds of this invention are primarily those withmetals, particularly alkali metals, e.g. sodium, potassium and the like;monoor poly-salts may be formed.

The compounds of the present invention have diuretic and saliuretic,particularly natriuretic properties and are intended to be used asdiuretic or saliuretic, particularly natriuretic agents having improvedand outstanding properties to relieve conditions of excessive water andsalt retention, for example, caused by kidney or heart ailments. Coupledwith the diuretic and saliuretic activities of the present compounds isa strong antihypertensive effect, which renders the compounds especiallyuseful as antihypertensive medicaments in hypertensive conditions, whichare coupled with water and salt retention, such as, for example, inheart ailments. Particularly outstanding diuretic and saliuretic effectsare shown by compounds of the formula in which R represents hydrogen,lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyland the like, or lower alkyl substituted by halogen, lower alkoxy, loweralkyl-mercapto, phenyl-lower alkyl-mercapto and the like, e.g.chloromethyl, dichloromethyl, ethoxymethyl, ethylmercaptoethyl,benzylmercaptoethyl and the like, lower alkenyl, e.g. l-propenyl and thelike, cycloalkyl containing from five to six ring carbon atoms, e.g.cyclo pentyl and the like, or phenyl-lower alkyl, e.g. benzyl,Z-phenylethyl and the like, R represents cyclo-oxa-alkyl (particularly,2-cyclo-oxa-alkyl) containing at most two atoms selected from the groupconsisting of oxygen and sulfur and from four to six carbon atoms asring members, R stands for halogen, e.g. fluorine, bromine, orparticularly chlorine, or halogeno-lower alkyl, e.g. trifluoromethyl,and sodium or potassium salts thereof. This group of compounds may berepresented by the compounds of the formulae s 2 mNo s R G H-(halogeno-lower alkyl) \N (/11- (phenyl-lower alkyl) in which compoundsR stands for chlorine or trifluoromethyl, and lower alkyl contains fromone to four carbon atoms, and R is defined as above. Particularly activecompounds are, for example,

6-chloro-2- (2-cyclo-oxapentyl) -3-methyl-7-sulfamyl-3 ,4-

dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-trifluoromethyl-2- (4-methyl-2-cyclo-oxapentyl -3-methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1 l-dioxide,

6-chloro-2- (Z-cyclo-oxapentyl -3-methyl-7-sulfamyl-3 ,4-

dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-trifluoromethyl-2- (4-methyl-2-cyclo-oxapentyl) -3-methyl-7-sulfarnyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1,1-dioxide,

6-chloro-2- 5-methyl-2-cyclo-oxapentyl) -3-isobutyl-2-methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiaZine-1,1-dioxide,

6-trifiuoromethyl-2- (2-cyclo-oxahexyl) -3-isobutyl-2-methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1 l-dioxide,

6-chloro-2- (2-methyl-Z-cyclo-oxahexyl)-3-dichloromethyl-2-methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-l,1-dioxide,

3-dichloromethyl-6-trifluoromethyl-2- (4-methyl-2-cyclooxahexyl)-7-sulfamyl-3,4-dihydro-2H-l ,2,4-benzothiadiazine-l,1-dioxide,

3-benzyl-6-chloro-2- 6-methyl-2-cyclo-oxahexyl)-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide,

3-benzyl-2- 6-phenyl-2-cyclo-oxahexyl)-6-trifluoromethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide,

2- (bicyclo [4,4,0] -2-oxa-3-decyl) -6-chloro-7-sulfamyl-3,4-

dihydro-ZH-l,2,4-benZothiadiaZine-1,l-dioxide,

2- (Z-benz [e] -cyclo-oxahexyl -3-ethyl-6-trifluoromethyl- 7-sulfamyl-3,4-dihydro-2H-l,2,4-benZothiadiaZine-1,1- dioxide,

6-chloro-3-ethyl-2- (2-cyclo-oxaheptyl -7-sulfamyl-3,4-

dihydro-2H-1,2,4-benzothiadiaZine-l,l-dioxide,

6-trifiuoromethyl-2-(2-cyclo-1,4-dioxahexyl)-7-sulfamyl- 3,4-dihydro-2I-I-1,2,4-benzothiadiaZine-1, l-dioxide,

6-chloro-3-ethyl-2-(Z-cyclo-1,4-oxathiahexyl) -7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide,

6-trifluoromethyl-2- (Z-cyclo-thiapentyl) -3-isobutyl-7-sulfamyl-3,4-dihydro-2H-l,2,4-benZothiadiaZine-1,1- dioxide,

6-chloro-2- (Z-cycIo-thiahexyl)-3-ethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide,

2- Z-cyclol ,4-dithiahexyl) -3-ethyl-6-trifluoromethyl-7- sulfamyl-3,4-dihydro-2H-l,2,4-benZothiadiazine-1,1- dioxide,

6-ehloro-2- (2-cyclo-oxapentyl) -7-sulfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-1, l-dioxide,

2- (4-methyl-2-cyclo-oxapentyl) -6-trifluoromethyl-7sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide,

6-chloro-2- (2-cyclo-oxahexyl) -7-sulfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-trifluoromethyl-2- Z-cyclo-oxahexyl -7-sulfamyl-3,4-

dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-2- (2-cyclo-oxaheptyl -7-sulfamyl-3,4-dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxide,

-trifluoromethyl-Z- (Z-cyclo-oxaheptyl -7-sulfamyl-3,4-

dihydro-ZH-1,2,4-benzothiadiazi ne-1,1-dioxide,

2-(2-cyclo-1,4-dioxapentyl)-6-chloro-7-sulfamyl-3,4-dihydro-2H-l,2,4-benzothiadiazine-1,1-dioxide,

2- (Z-cyclo-1,4-oxathiahexyl)-6-trifluoromethyl-7-sulfamyl-B'A-dihydro-ZH-l,2,4,-benzothiadiazine-l,l-dioxideand the like,

each of which is substituted in the 3-position by a lower cyclo-alkylgroup containing oxygen and/ or sulfur atoms as ring members andadvantageously having from four to six carbon atoms and at most twohetero (S or O) ring members.

The new compounds of this invention may be used as medicaments in theform of pharmaceutical preparations, which contain the new2-substituted-3,4-dihydro-2H-l,2, 4-benzothiadiazine-l,l-dioxidecompounds or the salts thereof in admixture with a pharmaceuticalorganic or inorganic, solid or liquid carrier suitable for enteral, e.g.oral, or parenteral administration. For making up the preparations therecan be employed substances which do not react with the new compounds,such as water, gelatine, lactose, starches, stearic acid, magnesiumstearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums,waxes, propylene glycol, polyalkylene glycols or any other known carrierfor medicaments. The pharmaceutical preparations may be in solid form,for example, as capsules, tablets or dragees, or in liquid form, forexample, as solutions, suspensions or emulsions. If desired, they maycontain auxiliary substances such as preserving agents, stabilizingagents, wetting or emulsifying agents, salts for varying the osmoticpressure or buffers. They may also contain, in combination, othertherapeutically useful substances; particularly useful areantihypertensive compounds, such as Rauwolfia alkaloids, e.g. reserpine,rescinnamine or deserpidine, semisynthetic Rauwolfia alkaloids, e.g.syrosingopine and the like, Veratrum alkaloids, e.g. germine,protoveratrine and the like, synthetic antihypertensive compounds, e.g.hydralazine, dihydralazine and the like, or ganglionic blockers, e.g.chlorisondamine and the like.

The compounds of the present invention may be prepared according tomethods which are known in themselves.

Thus, compounds of the formula z// in which R R R and R have thepreviously-given meaning may be prepared, for example, by treating a3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide of the in which R Rand R have the previously-given meaning, or an alkali metal saltthereof, with a cycloalkene containing oxygen and/ or sulfur atoms asring members, which is capable of introducing the radical R in thepresence of a condensing agent, and isolating the desired product, and,if desired, converting a resulting salt into the free compound, and/ or,if desired, converting a free compound into a salt thereof.

The above-mentioned lower cycloalkene reagents are more particularlyZ-cycloalkenes containing at most two atoms selected from the groupconsisting of oxygen and sulfur and from four to six carbon atoms asring members. Such compounds are, for example, 2-cyclo-oxaalkenescontaining from four to six carbon atoms as ring members, such asdihydrofurans (Z-cyclo-oxapentenes), e.g. dihydrofuran(Z-cyclo-oxapentene), 4-methyl-dihydrofuran(4-methyl-2-cyclo-oxapentene), or S-methyl-dihydrofuran(5-methyl-2cyclo-oxapentene) and the like, dihydropyrans(2-cyclo-oxahexenes), e.g. dihydropyran (2-cyclo-oxahexene),Z-methyl-dihydropyran (Z-methyl- 2-cyclo oxahexene),4-methyl-dihydropyran (4-methyl-2- cyclo-oxahexene),6-methyl-dihydropyran (6-methyl-2- cyclo-oxahexene),6-phenyl-dihydropyran (6 phenyl 2- cyclo-oxahexene),hexahydro-benz[eJdihydropyran (bicyclo[4,4,0]-2-oxa-3-decene) or2-benz[e]dihydr0pyran (2-benz[e]cyclo-oxahexene) and the like,2-cyclo-oxaheptenes, e.g. 2-cyclo-oxaheptene and the like,dihydrodioxines (2-cyclo-dioxahexenes), such as dihydro-1,4- dioxines(2-cyclo-l,4-dioxahexenes), e.g. dihydro-1,4-dioxine(Z-cyclo-1,4-dioxahexene) and the like, dihydrooxathiins(2-cyclo-oxathiahexenes), such as dihydro-l,4- oxathiins(2-cyclo-1,4-oxathiahexenes), e.g. dihydro-1,4- dioxathiin(Z-cyclo-l,4-oxathiahexene) and the like, dihydrothiophenes(Z-cyClo-thiapentene), e.g. dihydrothiophene (2-cyclo-thiapentene) andthe like, dihydrothiapyrans (2-cyclo-thiahexenes), e.g. dihydrothiapyran(2- cyclo-thiahexene) and the like, or dihydro-dithiins (2-cyclo-dithiahexenes), such as dihydro-l,4-dithiins (2-cyclo-l,4-dithi&exenes), e.g. dihydro-l,4-dithiin (2-eyclo-1,4-dithiahexene) and the like.

These reagents, particularly the 2-cyclo-oxa-alkenes containing fromfour to six carbon atoms as ring members, such as dihydropyrans, e.g.dihydropyran, are reacted with the deserpidate compound in the presenceof a condensing reagent, particularly an acidic condensing reagentrepresented by a Lewis acid. Such Lewis acids are, for example, mineralacids, e.g. hydrochloric, hydrobromic or sulfuric acid (used inanhydrous form or as concentrated aqueous solutions), phosphoric acid(for example, in the form of polyphosphoric acid), phosphorousoxychloride, fluoboric acid (in the form of a highly concentratedaqueous solution), borontrifluoride (in the form of its etherate,particularly with diethyl ether), or a carbocyclic aryl sulfonic acid,such as a monocyclic carbocylic acid, especially p-toluene sulfonicacid, or similar reagents having Lewis acid properties, such as, forexample, cation exchange resins in acid form, e.g. sulfonic acid resins.

The reaction may be carried out in the absence of a solvent, whereby anexcess of a liquid cycloalkene may serve as the solvent, or in thepresence of an inert solvent. Such solvents are, for example,carbocyclic aryl hydrocarbons, such as monocyclic carbocyclic arylhydrocarbons, e.g. benzene or toluene and the like, others, e.g.diethylether or tetrahydrofuran and the like, lower alkanoncs, e.g.acetone or ethyl methyl ketone and the like, formamides, e.g. formamideor N,N-dimethylformamide and the like.

The desired product is isolated from the reaction mixture according tousual methods; ordinarily, a resulting precipitate, if necessary afterconcentration of the reaction mixture, is filtered off and is purifiedby recrystallization.

The 3,4-dihydro-2H-1,4-benzothiadiazine-1,l-dioxides used as thestarting materials are known or may be prepared according to proceduresused for the known analogs. For example, an aniline compound of theformula in which R and R have the previously-given meaning is reactedwith an aldehyde of the formula R CHO, in which R has thepreviously-given meaning, or a reactive derivative thereof, to form thedesired 3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,l-dioxide, which maythen be condensed with the desired cyclo-oxa-alkene or cyclo-azaalkeneto yield the R-R '-substituted product, R having the previously-givenmeaning.

Although the disulfamyhaniline compound is preferably treated withapproximately an equivalent amount of the aldehyde, particularly whenformaldehyde or a reactive derivative, e.g. a polymer thereof is used,an excess of an aldehyde other than formaldehyde or a derivative thereofmay be present. The reaction may advantageously be carried out in thepresence of a small amount of an acid, for example, a mineral acid, e.g.hydrochloric, hydrobrornic acid, sulfuric acid and the like, if desired,in anhydrous form. An acid is necessary, if the aldehyde is present inthe form of a reactive derivative, such as a polymer or an acetal,thereof. It may also be performed in the absence of a condensingreagent, or in the presence of a base, such as an alkali metalhydroxide, e.g lithium, sodium or potassium hydroxide, whereby thealdehyde is used in its reactive form. As mentioned above, the aldehydemay also be given into the reaction medium in a form which yields thedesired reactant in situ. Thus, f r example, an acetal of an aldehyde RCHO with lower alkanols, for example, with methanol or ethanol, may beused in the presence of a mineral acid; such acetals are, for example,1,1-dimethoxyethane, 1,l-dimethoxy-isobutane, 1,1-diethoxy-isobutane,2,2-dichloro-1,l-dimethoxyethane, 2,2-dichlorol,l-diethoxy-ethane andthe like. Formaldehyde may also be employed in the form of a polymer,such as, for example, paraformaldehyde and the like or anotherformaldehyde furnishing reagent, e.g. hexamethylenetetramine and thelike; acetaldehyde may be present in the form of a polymeric substanceyielding acetaldehyde under the condition of the reaction, e.g.metaldehyde and the like.

The reaction is preferably carried out in the presence of a solvent, forexample, an ether, e.g. p-dioxane, diethyleneglycol dimethylether andthe like, a lower alkanol, e.g. methanol, ethanol and the like, aformamide, e.g. dirnethylformamide and the like, or an aqueous mixtureof such solvents or water. If desired, it may be completed at anelevated temperature, for example, on the steam bath or at the boilingtemperature of the sol vent and, if necessary, the reaction may beperformed under increased pressure or in the atmosphere of an inert gas,e.g, nitrogen.

The 5-R -2,4-disulfamyl-anilines, used as the intermediates in the abovereaction are known or, if new, may be prepared according to knownprocedures.

The compounds of the present invention may also be prepared by reactinga 2,4-disulfamyl-aniline of the formula in which R R and R have thepreviously-given meaning, with an aldehyde of the formula R CHO, inwhich R has the above-given meaning, or a reactive derivative thereof,and, if desired, carrying out the optional steps.

The above reaction may be performed according to thepreviously-described method for the preparation of 2-unsubstituted3,4-dihydro-2H-l,2,4-benzothiadiazine-l,l-dioxides used as the startingmaterials in the first modifimtion of the process of this invention. Forexample, the two reactants may be heated in a solution using one of thepreviously-described diluents, if desired, in the pres ence of a base asa condensing reagent. As pointed out, the aldehyde may also be used inthe form of an appropriate reactive derivative.

The 2 (N-R '-sulfamyl) 4 sulfamyl-5-R -N-R analine compounds used as thestarting materials, are new and are intended to be included within thescope of the invention. The compounds of the formula in which R R and Rhave the previously-given meaning, may be obtained by reacting ananiline-2,4-disulfonyl halide of the formula in which R and R have thepreviously-given meaning, and Hal stands for halogen, particularlychlorine, with approximately two molar equivalents of an amine of theformula R '--NH in which R has the above-given meaning, and reacting theresulting compound of the formula in which R R R and Hal have thepreviously-given meaning, with ammonia.

The first step in the above procedure may be carried out in a solvent;halogenated alkanes, particularly chloroform, methylene chloride and thelike, or lower alkanones, e.g. acetone and the like, may be used asdiluents. Amines of the formula R -NH are those in which the term R hasthe meaning given above.

The resulting 2-(N-R -sulfamyl)-aniline-4-sulfonyl halide compound maybe separated from any 2,4-di-(N- R '-sulfamyl)-aniline formed in thereaction, for example, on the basis of their different solubilities in agiven solvent, e.g. the diluent used in the reaction. Thus, the2,4-bis-(N-R '-sulfamyl)-aniline compound may precipitate from thereaction mixture and be removed by filtration, whereas the desired2-(N-R -sulfamyl)-aniline-4-sulfonyl halide compound may be recoveredfrom the filtrate.

The resulting 2-(N-R '-sulfamyl)aniline-4-sulfonyl halide derivative isthen reacted with ammonia. Liquid ammonia may be used and maysimultaneously serve as a diluent, or the compound may be dissolved inan organic solvent, e.g. acetone and the like, or less favorably, inwater, and be treated with concentrated aqueous ammonia, to give thedesired 2-(N-R -sulfamyl)-4-sulfamylaniline compound.

It may also be possible to omit the separation of the desired 2-(N-R'-sulfamyl)-aniline-4-sulfonyl halide from any 2,4-bis-(N-R'-sulfamyl)-aniline compound simultaneously formed as a by-product; aresulting mixture may be reacted directly with ammonia directly andseparation of the two products may be achieved after such treatment.

Especially useful as intermediates are the compounds of the formula R3NH:

members, as enumerated above.

Also new and valuable as intermediates are the compounds of the formulain which R R R and Hal have the previously-given meaning, which areformed in the two-step synthesis for the preparation of the startingmaterials. A preferred group of such new intermediate compounds arethose of the formula in which R and R have the meaning given above.

Also included within the scope of the present invention are thecompounds of the formula in which R R R and R have the previously-givenmeaning, and R stands for aliphatic hydrocarbon, substituted aliphatichydrocarbon or carbocyclic aryl-lower aliphatic hydrocarbon, or metal,particularly alkali metal, salts thereof.

The compounds of the above-given formula have diuretic and saliuretic,particularly natriuretic properties and are intended to be used asdiuretic or saliuretic, particularly natriuretic agents having improvedand outstanding properties to relieve conditions of excessive water andsalt retention, for example, those connected with kidney or heartailments. Coupled with the diuretic and saliuretic activities of thesecompounds is a strong antihypertensive effect, which renders thecompounds especially useful as antihypertensive medicaments inhypertensive conditions, which are coupled with water and saltretention, such as, for example, in heart ailments. Particularlyoutstanding diuretic and saliuretic effects are shown by compounds ofthe formula in which R represents hydrogen, lower alkyl, e.g. methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, or loweralkyl substituted by halogen, lower alkoxy, lower alkyl-mercapto,phenyl-lower alkyl-mercapto and the like, e.g. chloromethyl,dichloromethyl, ethoxymethyl, ethylmercaptoethyl, benzylmercaptoethyland the like, lower alkenyl, e.g. l-propenyl and the like, cycloalkylcontaining from five to six carbon atoms as ring members, e.g.cyclopentyl and the like, or phenyl-lower alkyl, e.g. benzyl, 2-phenylethyl and the like, the radical R stands for lower cycloalkylcontaining oxygen and/ or sulfur atoms as ring members andadvantageously from four to six carbon atoms and at most two atomsselected from the group consisting of sulfur and oxygen as ring membersand R stands for lower alkyl containing from one to four carbon atoms,e.g. methyl, ethyl, n-propyl, isoproyl, nbutyl, isobutyl and the like,allylic lower alkenyl containmg allyl, 3-methyl-allyl and the like, orphenyl-lower alkyl, in which lower alkyl contains from one to fourcarbon atoms, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the fromthree to five carbon atoms, e.g. allyl, Z-methyl- 13 like, and R standsfor halogen, e.g. fluorine, bromine, or particularly chlorine, orhalogeno-lower alkyl, e.g. trifluoromethyl, and sodium or potassiumsalts thereof. This group of compounds may be represented by thecompounds of the formula aza eyeloalkyl in which formulae R representschlorine or trifluoromethyl, lower alkyl contains from one to four andlower alkenyl from three to five carbon atoms, as well as compounds ofthe above formulae, which contain in the 3- position a lower alkylradical containing from one to four carbon atoms, particularly methyl,ethyl, isobutyl and the like, halogeno-lower alkyl, in which lower alkylcontains from one to four carbon atoms, e.g. chloromethyl,dichloromethyl and the like, or phenyl-lower alkyl, in which lower alkylcontains from one to four carbon atoms, e.g. benzyl, l-phenylethyl,2-phenylethyl and the like.

Similarly, as with the previously-described compounds containing anN-unsubstituted sulfamyl group in the 7- position, the compounds of theabove formula may be formulated into pharmaceutical compositions forenteral, e.g. oral, or parenteral application; such compositions may beprepared according to known procedures, using standard vehicles andfillers.

The above-described compounds may be prepared, for example, by treatinga compound of the formula in which R R R and R have the previously-givenmeaning, with a reactive ester of an alcohol of the formula R "'OH, inwhich R has the above-given meaning, or treating a compound of theformula in which R R R and R have the previouslygiven meaning, with analdehyde of the formula R CHO, in which R has the above-given meaning,or a reactive derivative thereof and, if desired, converting a resultingsalt into the free compound, and/ or, if desired, converting a freecompound into a salt thereof.

The above reactions are carried out according to thepreviously-described procedures. For example, an ester of a reactivealcohol of the formula R "OH is particularly an ester with a strongacid, particularly a mineral acid, e.g. hydrochloric, hydrobromic,sulfuric acid and the like, or an organic sulfonic acid, e.g. methanesulfonic, ethane sulfonic, Z-hydrOXy-ethane sulfonic, p-tolu- 14 enesulfonic acid and the like; such esters are preferably reacted with asalt, particularly an alkali metal salt of the starting material. Or, analdehyde of the formula R CHO may also be used in the form of an acetalwith a lower alkanol, e.g. methanol, ethanol and the like. Formaldehydeor acetaldehyde may be present as a polymeric form thereof, e.g.paraformaldehyde, metaldehyde and the like; other reactive formsfurnishing formaldehyde are, for example, hexamethylenetetramine and thelike. Reactions with such acetals and polymeric forms of aldehydes arecarried out in the presence of an acid, for example, a mineral acid,e.g. hydrochloric acid and the like.

Compounds of the formula in which R R R R and R have the previouslygivenmeaning, and R and R stand for the identical group, may also be preparedby reacting a compound of the formula in which R R and R have theabove-given meaning with an excess of a reactive ester of an alcohol ofthe formula R 'OH, in which R has the previously-given meaning, andisolating the desired compound, and, if desired, carrying out theoptional steps.

The reaction may be performed as previously shown; the desired productis separated from any simultaneously formed3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide containing anunsubstituted sulfamyl group in the 7-position, on the basis ofdiffering solubilities in solvents, for example, by recrystallizationand the like.

The resulting product may be obtained in the form of the free compoundor as a salt thereof. An alkali metal salt may be converted into thefree compound by treatment with an aqueous acidic reagent, such as amineral acid, e.g. hydrochloric, sulfuric acid and the like. A freecompound may be converted into an alkali metal salt, for example, bytreatment with an alkali metal hydroxide, e.g. sodium or potassiumhydroxide, in a solvent, such as in a lower alkanol, e.g. methanol,ethanol and the like, or in water and evaporating the solvent. Monoorpoly-salts may be obtained.

Any resulting racemate may be converted into the antipodes thereofaccording to methods used for resolving racemates.

The following examples illustrate the invention; they are not to beconstrued as being limitations thereon. Temperatures are given indegrees centigrade.

Example 1 To 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamy1-l,2,4-benzothiadiazine-l,l-dioxide in 35-40 cc. of warm acetone is added 0.84g. dihydropyran and two drops concentrated hydrochloric acid. Thesolution is allowed to remain at room temperature overnight, thenconcentrated to dryness in vacuo. A small amount of ether is added tothe residue and white crystals are obtained, yielding, whenrecrystallized from acetone, 600 mg. 6-chloro-3,4-dihydro- 7 sulfamylZ-(tetrahydro-Z-pyranyl)-1,2,4-benzothiadizine-1,1-dioxide; M.P. 23l232d.

[By substituting an equivalent amount of 6-trifluor0- methyl-3,4-dihydro7 sulfamyl-l,2,4-be11zothiadiazine- 1,1-dioxide for the6-chloro-3,4-dihydro-7-sulfamyl-1,2,4- benzothiadiazine-l,l-dioxide andfollowing the procedure 15 given above, the corresponding6-trifluoromethyl compound may be obtained. Using the identicalprocedure and any of the other cyclooxa-alkyl or cyclo-aza-alkylreactants named above, corresponding products may be obtained, as isevident below.]

Example 2 2.55 g. of6-chloro-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide in 40cc. of warm acetone is treated with 0.9 g. 4-methyl-dihydropyran and twodrops concentrated hydrochloric acid. The solution is allowed to remainat room temperature overnight and then concentrated to dryness in vacuo.A small amount of ether is added to the residue and white crystals ofthe product, 6-chloro-3,4-dihydro 7 sulfamyl 2 (4methyl-tetrahydro-2-pyranyl)-1,2,4-benzothiadiazine-1,1-dioxide, areobtained.

[By substituting an equivalent amount of 6-trifluoromethyl-3,4-dihydro 7sulfamyl-l,2,4-benzothiadiazine- 1,1-dioxide for the6-chloro-3,4-dihydro-7-sultamyl-l,2,4- benzothiadiazine-1,1-dioxide andfollowing the procedure given above, the corresponding 6-trifluoromethylcompound may be obtained] Example 3 2.55 g. of6-chloro-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide in 35cc. of warm acetone is treated with 1 g. 6-ethoxy-dihydropyran and twodrops concentrated hydrochloric acid. After remaining overnight at roomtemperature, the solution is concentrated to dryness in vacuo. Theproduct, 6-chloro-3,4-dihydro- 2-(6-ethoxy-tetrahydro 2 pyranyl) 7sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide, is collected andrecrystallized from acetone.

[By substituting an equivalent amount of 6-trifiuoromethyl-3,4-dihydro 7sulfamyl-l,2,4-benzothiadiazine- 1,1-dioxide for the6-chloro-3,4-dihydro-7-sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide andfollowing the procedure given above, the corresponding 6-trifluoromethylcompound may be obtained] Example 4 3.2 g. of6-chloro-3-cyclopentylmethyl-3,4-dihydro-7-sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide in 40 cc. of warm acetone istreated with 0.84 g. dihydropyran and two drops concentratedhydrochloric acid. The solution is allowed to remain at room temperatureovernight. The product is then collected and recrystallized fromethanol-Water to produce the pure6-chloro-3-cyclopentylmethyl-3,4-dihydro-7-sulfamyl-2(tetrahydro-2-pyranyl)- 1 ,2,4-benzothiadiazine-1,l-dioxide.

[By substituting 6-trifluoromethyl-3-cyclopentylmeth yl-3,4-dihydro 7sulfamyl 1,2,4 benzothiadiazine-l,1- dioxide for the6-chloro-3-cyclopentylmethyl-3,4-dihydro- 7-sulfamyl 1,2,4benzothiadiazine-l,l-dioxide reactant used in this example, thecorresponding trifluoromethyl product may be obtained] Example 3.8 g. of3-benzylmethyl-6-chloro-3,4-dihydro-7-sulfamyl-l,2,4-benzothiadiazine-l,l-dioxideis dissolved in 50 cc. of warm acetone. This is treated with 1 g.4,6-dimethyl-dihydropyran and two drops concentrated hydrochloric acid.After remaining overnight at room temperature, the solution isconcentrated to dryness in vacuo. The residue is recrystallized fromethanol to produce the pure 3-benzylmethyl-6-chloro 3,4dihydro-7-sulfamyl-2- (4,6-dimethyl 2 pyranyl) 1,2,4benzothiadiazine-1,ldioxide.

[By substituting 3-benzylmethyl-6-trifiuoromethyl-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide for the3-benzylmethyl-6-chloro-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide used in this example, the correspondingtrifluoromethyl compound may be obtained.]

15 Example 6 3.2 g. of6-chloro-3-dichloromethyl-3,4-dihydro-7-sulfarnyl-l,2,4-benzothiadiazine-l,l-dioxidein cc. of warm acetone is treated with 0.84 g. dihydropyran and twodrops concentrated hydrochloric acid. The solution is allowed to remainovernight at room temperature and then concentrated to dryness in vacuo.The residue thus obtained is recrystallized from ethanol-water toproduce the pure 6-chloro-3-dichloromethyl 7sulfamyl-Z-(tetrahydro-Z-pyranyl)-l,2,4-benzothiadiazine-1,l-dioxide.

[By substituting 6-trifluor0methy1-3-monochlorometl1 yl-3,4-dihydro 7sulfamyl 1,2,4 benzothiadiazine-l,1- dioxide for the6-chloro-3-dichloromethyl-3,4-dihydro-7-sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide used in this example, thecorresponding 3-monochloromethyl compound may be obtained. Substitutionof the 6-chloro-3- monochloromethyl (or 3-dichloromethyl) reactants forthe one used in this example, will yield the correspondingtrifluoromethyl derivatives] Example 7 2.75 g. of3-cyclopentylmethyl-3,4-dihydro-7-sulfamyl-6-trilluoromethyl-1,2,4-benzothiadiazine-1,l-dioxide is dissolved in cc.of warm acetone and then treated with 0.84 g. dihydropyran and two dropsconcentrated hydrochloric acid. After remaining overnight the solutionis evaporated to one-half its volume, the crystals collected andrecrystallized from ethanol-water to produce the pure3-cyclopentylmethyl 3,4dihydro-7-sulfamyl-6-trifiuoromethyl-2-(tetrahydro 2pyranyl)-1,2,4-benzothiadiazine-1,1-dioxide.

1 What is claimed is:

l. A member of the group consisting of 3,4-dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxides of the formula in which Rrepresents a member of the group consisting of hydrogen, lower alkyl,lower alkyl substituted by halo gen, halo-lower alkyl, loweralkoxy-lower alkyl, lower alkyl-rnercapto-lower alkyl, phenyl-loweralkyl-mercaptolower alkyl, lower alkenyl, cycloalkyl having from five tosix ring carbon atoms and phenyl-lower alkyl, R stands for 2-cycloalkylhaving four to six carbon atoms and at least one and at most two atomsof the group consisting of oxygen and sulfur as ring members, and Rrepresents a member of the group consisting of halogen and halogen-loweralkyl, and alkali metal salts thereof.

2. 6 chloro 2-R-7 sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide, wherein R is 2-tetrahydro-2- pyranyl.

3. 6 chloro 2-R-7 sulfamyl-3,4-dihydro-2H-l,2,4-benzothiadiazine-1,1-dioxide, wherein R is4-methyl-tetrahydro-Z-pyranyl.

4. 6 trifluoromethyl 2-R-7 sulfamyl-3,4-dihydro-ZH-1,2,4-benzothiadiazine-l,l-dioxide, in which R is 2- cyclo-oxaalkylhaving from four to six carbon atoms.

5. -chloro-3-halogeno-lower alkyl-2-R-7-sulfamyl-3,4-dihydro-ZH-1,2,4-benzothiadiazine-l,l-dioxide, in which lower alkyl hasfrom one to four carbon atoms and R is 2-cyclooxaalkyl having from fourto six carbon atoms.

6. 6 trifiuoromethyl-3-halogeno-lower alkyl 2-R-7- sulfamyl 3,4dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxide, in which lower alkyl hasfrom one to four carbon atoms and R is 2-cyclo-oxaalkyl having from fourto six carbon atoms.

7. 6-chloro-2-R-3-phenyl-lower alkyl-7-sulfamyhydro-2H-1,2,4-benzothiadiazine-l,l-dioxide, in which lower alkyl hasfrom one to four carbon atoms and R is y -oxaalkyl having from four tosix carbon atoms.

3,133,918 17 18 8. 6 trifiuoromethy1-2-R-3-phenyl-10wer alkyl 7 suI-References Cited in the file of this patentfamyI-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1 diOX- UNITED STATESPATENTS ide, in which lower alkyl has from one to four carbon atoms andR is zmrmhydmpyranyli 1,911,719 Schwefzer et a1 May 30, 1933 9. 6chl0ro-2,3-bis-(tetrahydro-Z-pyranyl)-7-su1famy1- 5 g g et a 3,4-dihydro-2H-1,2,4-benzothiadiazine-1, 2809194 n i 5 10. 6n-ifluoromethy1-2,3-bis-(tetrahydr -py y 2910475 oveno c 7 19597-sulfamyl 3,4 dihydm-ZH-l,2,4-benzothiadiazinel,1- Nove 2 dioxidi2,910,4588 Novello Oct. 27, 1959

1. A MEMBER OF THE GROUP CONSISTING OF3,4-DIHYDRO2H-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDES OF THE FORMULA